Taking the toxin out of your cancer treatment

BANGALORE: RA Mashelkar met Shiladitya Sengupta when he went to Harvard University in 2007 as a visiting professor. Young, ambitious and idealistic, Sengupta had set up his lab for nanomedicine at Harvard with multiple goals, one of which was to find ways of making healthcare affordable.

Mashelkar, now a National Research Professor, had similar aims and he immediately took a liking to this fiercely-nonconformist researcher. In his lab, Sengupta had gathered a set of students with a comparable bend of mind, who wanted to move back to India and use science for development.

They began to brainstorm during Mashelkar's annual four-week visits to Harvard, specifically on methods to decrease the toxicity of cancer drugs.

Cancer drugs, in the forms they are used now, can be used only in limited doses because of toxicity. But patients often need high doses and so many cancer drugs end up not finishing their job. Sengupta looked at toxic platinum-based drugs - that are very effective - to find a method to improve efficacy while reducing toxicity.

Cisplatin, a wonderfully-effective but toxic drug, was their first candidate. Its patent was to expire in 2013. A modified Cisplatin would give them the intellectual property for two decades.

"I have been thinking for a while of using high technology for the poor," says Mashelkar, "and improving existing cancer drugs at low cost was a good example."

However, several researchers had been working on the problem and not getting a good solution. Last week, this team published a paper - in the high-ranking journal PNAS - that offered a solution to drug toxicity. They increased the size of Cisplatin by joining it with cholesterol.

The enlarged molecules are too big to get into the body tissues and damage them but cancer cells have larger pores that let them through. In lab studies, the conjugate drug was shown to be far less toxic, but highly effective.

Sengupta and Mashelkar have set up a Delhi-based company, Invictus Oncology, to take this modified Cisplatin to the market. Invictus had licensed the technology from the non-profit Partners Healthcare, founded by the Brigham And Women's Hospital in Harvard, where the research was carried out.

"We have completely de-risked our business model," says Monideepa Roy, group leader of pre-clinical biology at Invictus. The company has received $1 million in seed funding from Navam Capital.

Cisplatin, being a drug already in use, may not require full clinical trials when modified. Cholesterol is a molecule found in the body and known to be non-toxic. The cholesterol-Cisplatin conjugate is thus unlikely to be more toxic that Cisplatin itself.

"We wanted to use something that is already in the body," says Sudipta Basu, who had worked on the problem with Sengupta as a post-doctoral researcher. "It is then easier to get regulatory approvals." Basu, along with his wife Poulomi Sengupta, had worked at the Harvard lab.

Platinum-based drugs form a $3-billon market. It includes, other than Cisplatin, Carboplatin and Oxaliplatin - two less toxic but less potent drugs. Invictus expects approvals for accelerated clinical trials for the Cisplatin-cholesterol conjugate.

This means they can compress the development time to about five or six years and prepare for a launch in 2017-2018. "We hope this will be the first blockbuster drug developed in India," says Sengupta. The new drug, if it hits the market, would be far less expensive than Cisplatin expanding the market.

"Big companies will be interested in modified drugs because they offer significant value at lower cost," says TS Sridhar, professor of molecular medicine at St John's Medical College in Bangalore.

In fact, the power of their method goes beyond Cisplatin or platinum-based drugs: it could be used in reducing toxicity of other anti-cancer drugs.

Scientists have been trying to reduce drug toxicity through several methods. One way was to tinker with the molecule itself, changing structure of the molecule so that it does not cause the toxic reaction. For Cisplatin, this meant making Cisplatin less damaging to the DNA.

Carboplatin and Oxaliplatin are two drugs that have resulted from this approach. Unfortunately, platinum-based drugs are effective against cancer precisely because they stop the DNA from replicating. Tinkering with this property also reduces the drug's effectiveness.

Another popular method is to enclose the drug inside molecular balloons to shield it from vital organs. These balloons or capsules are supposed to go the cancer tissue, get inside and then release the drug. In practice, however, this method is hard to implement making the drug less effective.

Sengupta's team didn't use either of these approaches but focused on two methods also available to researchers: size exclusion and self assembly.